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J Immunol. 2019 Mar 15;202(6):1815-1825. doi: 10.4049/jimmunol.1801477. Epub 2019 Feb 1.

MEK2 Negatively Regulates Lipopolysaccharide-Mediated IL-1β Production through HIF-1α Expression.

Author information

1
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201.
2
Division of Critical Care, Department of Pediatrics, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201.
3
The Francis Crick Institute, London NW1 1AT, United Kingdom.
4
Centre de Recherche sur le Cancer de l'Université Laval, L'Hôtel-Dieu de Québec, Quebec City, Quebec, Canada; and.
5
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201; ay6003@wayne.edu.
6
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201.

Abstract

LPS-activated macrophages require metabolic reprogramming and glucose uptake mediated by hypoxia-inducible factor (HIF)-1 α and glucose transporter 1 (Glut1) expression for proinflammatory cytokine production, especially IL-1β. This process is tightly regulated through activation of MAPK kinases, including the MEK/ERK pathway as well as several transcription factors including HIF-1α. Although MAPK kinase (MEK) 2 deficiency had no significant effect on NO, TNF-α, or IL-12 production in response to LPS challenge, MEK2-deficient murine bone marrow-derived macrophages (BMDMs) exhibited lower IL-10 production. Importantly, MEK2-deficient BMDMs exhibited a preserved ERK1/2 phosphorylation, higher HIF-1α and Glut1 levels, and substantially increased IL-1β as well as IL-6 production in response to LPS stimulation. Knockdown of HIF-1α expression via short interference RNA decreased the level of HIF-1α expression in MEK2-deficient BMDMs and decreased IL-1β production in response to LPS treatment. Furthermore, we performed gain of function experiments by overexpressing MEK2 protein in RAW264.7 cells. LPS stimulation of MEK2 overexpressed in RAW264.7 cells led to a marked decreased IL-1β production. Finally, we investigated the role of Mek1 and Mek2 double and triple mutation on ERK phosphorylation, HIF-1α expression, and IL-1β production. We found that MEK2 is the major kinase, which inversely proportionally regulates HIF-1α and IL-1β expression independent of ERK activation. Our findings demonstrate a novel regulatory function for MEK2 in response to TLR4 activation in IL-1β production through modulating HIF-1α expression.

PMID:
30710049
PMCID:
PMC6401293
[Available on 2020-03-15]
DOI:
10.4049/jimmunol.1801477

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